Antiviral 2,4-pyrimidinedione derivatives and process for the preparation thereof

ABSTRACT

2,4-pyrimidinedione derivatives of formula (I) having high antiviral activity against wild-type and mutant HIV-1 and low toxicity are useful for treating AIDS (I) wherein: R 1  is a C 6-10  aryl or C 3-10  heteroaryl group optionally having one or more substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  alkyl substituted with one or more halogen atoms, C 3-4  cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C 1-6  alkoxy, oximino, C 1-3  alkyloximino, O—(C 1-6  alkyl)-substituted oximino, C— 1-6  alkylcarbonyl, C 3-6  cycloalkylcarbonyl, hydroxymethyl, azidomethlyl, C 1-6  alkoxymethyl, C 1-6  acyloxynethyl, carbamoyloxymethyl, anminomethyl, N—(C 1-3  alkyl)aminomethyl, N,N-di(C 1-3  alkyl)aminomethyl, carboxy, C 1-6  alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, trifluoroacetamido, C 1-6  acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C 1-6  alkylcarbamoyl, di(C 1-6  alkyl)carbamoyl, aminocarbamoyl, dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl group optionally substituted with a C 1-6  alkyl or C 1-6  alkoxycarbonyl group; a tetrahydropyranyl group; or a tetrahydrofuryl group; R 2  is hydrogen, halogen, nitro, cyano, C 1-3  alkoxycarbonyl, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbamol, di(C 1-3  alkyl)carbamoyl, C 1-3  alkyl, C 3-6  cycloalkyl or benzyl; R 3  and R 4  are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino acetamido, trifluoroacetamido, azido, C 1-3  alkyl, C- 1-3  alkyl substituted with one or more halogen atoms, C 1-3  alkoxycarbonyl, carbamoyl C 1-3  alkylcarbamoyl, di(C 1-3  alkyl) carbamoyl or C- 1-3  alkoxy; A is O or S; and Z is O, S, C═O, NH or CH 2 .

This application is a national stage entry under section 371 ofPCT/KR00/00166, filed on Mar. 3, 2000.

FIELD OF THE INVENTION

The present invention relates to novel pyrimidinedione derivatives,which are useful as an antiviral agent, particularly for treatingacquired immunodeficiency syndrome (AIDS), a process for the preparationthereof and a pharmaceutical composition containing same as an activeingredient.

DESCRIPTION OF THE PRIOR ART

Various compounds such as AZT (3′-azido-3′-deoxythymidine), DDC(2′,3′-dideoxycytidine), DDI (2′,3′-dideoxyinosine), D4T(3′-deoxy-2′,3′-didehydrothymidine) 3TC(lamivudine), Ziagen, Nevirapine,Sustiva, Delavirdine, Indinavir, Ritonavir, Viracept, Saquinavir andAgenerase have been reported to have the ability, albeit limited, toinhibit the reproduction of AIDS virus. However, they are also known tocause undesirable side effects due to their toxicity as well as toinduce the mutation of the virus, thereby increasing the resistance ofthe virus.

In order to minimize such problems, therefore, many attempts have beenmade. For example, there have been reported 2,4-pyrimidinedionederivatives having 1-alkoxymethyl substituents {J. Med. Chem., 35, 4713(1992); J. Med. Chem., 35, 337 (1992); J. Med. Chem., 34, 1508 (1991);J. Med. Chem., 34, 1394 (1991); J. Med. Chem., 34, 349 (1991); MolecularPharm., 39, 805 (1991); Tet. Lett., 35, 4531 (1994); J. Med. Chem., 38,2860 (1995); Nucleosides and Nucleotides, 14, 575 (1995); J. Med. Chem.,39, 2427 (1996); J. Med. Chem., 42, 4500 (1999); EP 0,449,726 A1; EP0,420,763 A2; U.S. Pat. No. 5,278,167; U.S. Pat. No. 5,318,972; U.S.Pat. No. 5,461,060; WO95/18109 A1; and U.S. Pat. No. 5,112,835}; 1-allylor propargyl substituents (U.S. Pat. No. 5,747,500); and1-cyclopentenylmethylene substituents (U.S. Pat. No. 5,922,727).Although these compounds exhibit improved activity against humanimmunodeficiency virus (HIV), there exists a need to develope non-toxiccompounds having even higher potency against both wild-type and mutantHIV.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the present invention to providea novel compound having superior antiviral activity against bothwild-type and mutant HIV-1 as well as reduced toxicity.

It is another object of the present invention to provide apharmaceutical composition containing same.

It is a further object of the present invention to provide a process forthe preparation of said novel compound.

In accordance with one aspect of the present invention, there isprovided a novel 2,4-pyrimidinedione compound of formula(I) or apharmaceutically acceptable salt thereof:

wherein:

R¹ is a C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl group optionally having one ormore substituents selected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆ alkyl substituted with one or more halogen atoms, C₃₋₆cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C₁₋₆ alkoxy,oximino, C₁₋₃ alkyloximino, O—(C₁₋₆ alkyl)-substituted oximino, C₁₋₆alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl, hydroxymethyl, azidomethyl, C₁₋₆alkoxymethyl, C₁₋₆ acyloxymethyl, carbamoyloxymethyl, aminomethyl,N—(C₁₋₃ alkyl)aminomethyl, N,N-di(C₁₋₃ alkyl)aminomethyl, carboxy, C₁₋₆alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, trifluoroacetamido, C₁₋₆acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C₁₋₆alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl, aminocarbamoyl,dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl,triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl groupoptionally substituted with a c₁₋₆ alkyl or c₁₋₆ alkoxycarbonyl group; atetrahydropyranyl group; or a tetrahydrofuryl group;

R² is hydrogen, halogen, nitro, cyano, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, C₁₋₃ alkylcarbamoyl, di(C₁₋₃alkyl)carbamoyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or benzyl;

R³ and R⁴ are each independently hydrogen, halogen, hydroxy, cyano,nitro, amino, acetamido, trifluoroacetamido, azido, C₁₋₃ alkyl, C₁₋₃alkyl substituted with one or more halogen atoms, C₁₋₃ alkoxycarbonyl,carbamoyl, C₁₋₃ alkylcarbamoyl, di(C₁₋₃ alkyl)carbamoyl or C₁₋₃ alkoxy;

A is O or S; and

Z is O, S, C═O, NH or CH₂.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of formula(I) of the present invention, thepreferred are those wherein R¹ is a phenyl, pyridyl or N-oxopyridylgroup optionally having one or more substituents as listed informula(I).

The 2,4-pyrimidinedione compound of formula(I) may be prepared bycoupling a compound of formula(II) with a compound of formula(III), asshown in the Reaction Scheme A:

wherein:

R¹, R², R³, R⁴, A and Z have the same meanings as defined in formula(I)above;

Z′ is same as Z with the proviso that when A is oxygen, it can be aacetamido group; and

Y is a suitable leaving group, e.g., halogen, methanesulfonyl,toluenesulfonyl or trifluoromethanesulfonyl.

In Reaction Scheme A, the above reaction may be conducted in a solventin the presence of a base at a temperature ranging from −10 to 100° C.,wherein the molar ratio of the compound of formula(II) to the compoundof formula(III) may range from 1:0.8 to 1:1.2. Representative examplesof the base include lithium hydride, sodium hydride, potassium hydride,sodium carbonate, potassium carbonate and the like. Suitable for use inthis reaction is a polar solvent such as acetonitrile,hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO) anddimethylformamide(DMF).

The compounds of formula(II) may in some cases be prepared in accordancewith the procedure disclosed in U.S. Pat. No. 5,747,500. Alternatively,the compounds of formula(II) may be advantageously prepared in somespecial cases by the procedure illustrated in Reaction Scheme B:

In accordance with the method (i) in Reaction Scheme B, a compound offormula(IV) which may be prepared by way of a known method disclosed in,e.g., Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), issubjected to a coupling reaction with an arylformamide derivative in apolar solvent, e.g., dimethylformamide, in the presence of a strongbase, e.g., sodium hydride, under a nitrogen atmosphere to provide acompound of formula(V) (Step (a)). The compound of formula (V) isreacted with sodium methoxide in methanol to give a compound offormula(VI) (Step (b)). Then, the compound of formula(VI) isdemethylated and acetylated by the action of acetylbromide to provide acompound of formula(II-a) (Step (c)).

In the method (ii) of Reaction Scheme B, the compound of formula (IV) isreacted with a arylacetonitrile derivative in a polar solvent, e.g.,dimethylformamide, in the presence of a base, e.g., sodium hydride, toprovide a compound of formula(VII) (Step (d)), which is reacted withsodium methoxide in methanol to give a compound of formula(VIII) (Step(e)). Thereafter, the compound of formula(VIII) is reacted with a base,e.g., sodium hydride, in a polar solvent, e.g., dimethylformamide, inthe presence of oxygen to provide a compound of formula(IX) (Step (f)),which is hydrolyzed with an acid, e.g., hydrochloric acid, to provide acompound of formula(II-b) (Step (g)).

Each of the compounds of formula(II-a) and (II-b) may be converted toone of the compounds of formula(II) containing various substituents viafurther reactions.

In this regard, in accordance with another aspect of the presentinvention, there is provided a compound of formula(II):

wherein:

R′² is ethyl or isopropyl;

R′³ is nitro, amino, acetamido, trifluoroacetamido or C₁₋₃alkoxycarbonyl;

R′⁴ is methyl or halogen; and

Z″ is C═O, NH or acetamido.

Exemplary compounds of formula(I) of the present invention which can beprepared in accordance with the methods described above are listed inthe following Table 1:

TABLE 1 Comp. A Z R¹ R² R³ R⁴  1 O C═O

Isopropyl CH₃ CH₃  2 O C═O

Isopropyl CH₃ CH₃  3 O C═O

Isopropyl CH₃ CH₃  4 O C═O

Ethyl CH₃ CH₃  5 O C═O

Ethyl CH₃ CH₃  6 O C═O

Ethyl CH₃ CH₃  7 O C═O

Isopropyl CH₃ F  8 O C═O

Isopropyl CH₃ F  9 O C═O

Isopropyl CH₃ F 10 O C═O

Ethyl CH₃ F 11 O C═O

Ethyl CH₃ F 12 O C═O

Ethyl CH₃ F 13 O C═O

Isopropyl F F 14 O C═O

Isopropyl F F 15 O C═O

Isopropyl F F 16 O C═O

Ethyl F F 17 O C═O

Ethyl F F 18 O C═O

Ethyl F F 19 O C═O

Isopropyl Cl Cl 20 O C═O

Ethyl Cl Cl 21 O C═O

Isopropyl CH₃ Cl 22 O C═O

Isopropyl CH₂F CH₃ 23 O C═O

Ethyl CH₂F CH₃ 24 O O

Isopropyl CH₃ CH₃ 25 O O

Ethyl CH₃ CH₃ 26 O S

Isopropyl Cl Cl 27 O S

Isopropyl CH₃ CH₃ 28 O S

Ethyl CH₃ CH₃ 29 O C═O

Isopropyl CF₃ CF₃ 30 O C═O

Ethyl CF₃ CF₃ 31 O C═O

Isopropyl CF₃ CF₃ 32 O C═O

Isopropyl CH₃ H 33 O C═O

Ethyl CH₃ H 34 O C═O

Isopropyl H H 35 O C═O

Ethyl H H 36 O C═O

Isopropyl CH₃ CH₃ 37 O C═O

Ethyl CH₃ CH₃ 38 O C═O

Isopropyl CH₃ CH₃ 39 O C═O

Isopropyl CH₃ CH₃ 40 O C═O

Isopropyl CH₃ CH₃ 41 O C═O

Ethyl CH₃ CH₃ 42 O C═O

Ethyl CH₃ CH₃ 43 O C═O

Isopropyl CH₃ CH₃ 44 O C═O

Isopropyl CH₃ CH₃ 45 O C═O

Isopropyl CH₃ CH₃ 46 O C═O

Isopropyl CH₃ F 47 O C═O

Isopropyl CH₃ Cl 48 O C═O

Isopropyl Cl Cl 49 O C═O

Isopropyl CH₂F CH₃ 50 O C═O

Isopropyl CH₃ H 51 O C═O

Isopropyl CH₃ CH₃ 52 O C═O

Ethyl CH₃ CH₃ 53 O C═O

Ethyl CH₃ F 54 O C═O

Ethyl CH₃ CH₃ 55 O C═O

Isopropyl CH₃ CH₃ 56 O C═O

Isopropyl F F 57 O C═O

Isopropyl Cl Cl 58 O C═O

Isopropyl CH₂F CH₃ 59 O C═O

Isopropyl Cl CH₃ 60 O C═O

Ethyl CH₃ CH₃ 61 O C═O

Ethyl F F 62 O C═O

Isopropyl CH₃ CH₃ 63 O C═O

Isopropyl CH₃ Cl 64 O C═O

Isopropyl CH₃ NO₂ 65 O C═O

Isopropyl CH₃ NO₂ 66 O NH

Isopropyl CH₃ CH₃ 67 O NH

Ethyl CH₃ CH₃ 68 O C═O

Isopropyl CH₃ CH₃ 69 O C═O

Isopropyl CH₃ CH₃ 70 O C═O

Isopropyl CH₃ CH₃ 71 O C═O

Isopropyl CH₃ Cl 72 O C═O

Isopropyl CH₃ CH₃ 73 O C═O

Isopropyl CH₃ CH₃ 74 O C═O

Isopropyl CH₃ Cl 75 O C═O

Isopropyl CH₃ CH₃ 76 O C═O

Isopropyl CH₃ CH₃ 77 O C═O

Isopropyl CH₃ Cl 78 O C═O

Isopropyl CH₃ CH₃ 79 O C═O

Isopropyl CH₃ CH₃ 80 O C═O

Isopropyl CH₃ Cl 81 O C═O

Isopropyl CH₃ CH₃

Furthermore, the present invention encompasses, within its scope,pharmaceutically acceptable salts of the 2,4-pyrimidinedione compoundsof formula(I). Suitable pharmaceutically acceptable salts of thecompounds of formula(I) possessing strong antiviral activity againstwild-type and mutant HIV-1 may include alkali or alkaline earth metalsalts, e.g., sodium, potassium, magnesium and calcium salts thereof.

The present invention also includes within its scope pharmaceuticalcompositions comprising one or more of the compounds of formula(I) ortheir above-mentioned salts as the active ingredient, in associationwith pharmaceutically acceptable carriers, excipients or otheradditives, if necessary.

The pharmaceutical compositions of the invention may be formulated foradministration orally or by injection. The composition for oraladministration may take various forms such as tablets and gelatincapsules, which may contain conventional additives such as a diluent(e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose andglycine), a lubricant (e.g., silica, talc, stearic acid or its magnesiumand calcium salts and polyethylene glycol). In the case of the tabletform, the composition may further comprise a binder (e.g., magnesiumaluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose and polyvinyl pyrrolidone) and optionallya disintegrant (e.g., starch, agar and alginic acid or its sodium salt),absorbent, colorant, flavor, sweetener and the like. The composition forinjection may be an isotonic solution or a suspension.

The composition may be sterilized and/or contain an adjuvant such as apreservative, stabilizer, wetting agent, emulsifier, a salt forcontrolling an osmotic pressure and/or a buffer solution, and otherpharmaceutically effective materials.

The pharmaceutical compositions can be prepared by a conventionalmixing, granulating or coating method and may contain preferably about0.1 to 75%, more preferably about 1 to 50% of the active ingredient ofthis invention. The unit dosage of the composition suitable foradministering a person weighing about 50 to 70 kg may contain about to200 mg of the active ingredient.

The following Preparations and Examples are given for the purpose ofillustration only and are not intended to limit the scope of theinvention.

In the Preparations and Examples, unless otherwise specified, theevaporation was conducted under reduced pressure, preferably under apressure ranging from about to 100 mmHg.

Preparations

The compounds of formula(II) having the structures (A) to (U), (II-a-1),(II-a-2) and (II-b-1) shown in Table 2 together with their meltingpoints and NMR data were used in preparing respective compounds offormula (I) of the present invention.

Preparations 1 to 21

Each of the compounds having the specified structures (A) to (U) wasprepared in accordance with the procedure described in U.S. Pat. No.5,747,500.

Preparation 22: Synthesis of5-Isopropyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione(Compound (II-a-1))

Step 1) Synthesis of2,4-Dichloro-5-isopropyl-6-(3′,5′-dimethylphenylformylamido)pyrimidine

To a magnetically stirred DMF solution (80 ml) of3,5-dimethylformaniline (8.94 g, 60 mmol) cooled in an ice bath, 60%sodium hydride dispersion (2.88 g, 72 mmol) was added portionwise undera nitrogen atmosphere. After 10 min,5-isopropyl-2,4,6-trichloropyrimidine (16.2 g, 72 mmol) was addedthereto and the reaction mixture was allowed to warm to roomtemperature, followed by stirring for 24 hr. Ether was then added to thereaction mixture, and the organic layer was washed with water, driedover anhydrous magnesium sulfate, and filtered. The solvent was removedunder reduced pressure and the resulting residue was purified by flashchromatography (eluent-ether:hexane=1:15) to afford 3.3 g (yield 17%) ofthe title compound as a white solid.

M.p.: 151 to 153° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.12-1.24 (6H, m), 2.30(6H, s), 3.22 (1H, m), 6.72 (2H, s), 6.96 (1H, s), 8.70 (1H, s); m/z(EI) 338 (M⁺).

Step 2) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(3′,5′-dimethylphenylamino)pyrimidine

Sodium (1.02 g, 44 mmol) was added portionwise to a stirred anhydrousmethanol (40 ml) at room temperature under a nitrogen atmosphere toprepare sodium methoxide solution. The compound obtained in Step 1) (3g, 8.88 mmol) was added to the solution and the mixture was refluxed for4 hr. The reaction mixture was allowed to cool to room temperature andneutralized with excess ammonium chloride. The solvent was removed underreduced pressure and the resulting residue was purified by flashchromatography (eluent-ethyl acetate:hexane=1:15) to afford 2.69 g(yield 97%) of the title compound as a white solid.

M.p.: 126 to 127° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.31 (6H, d, J=7.1 Hz),2.31 (6H, s), 3.12 (1H, m), 3.92 (3H, s), 3.93 (3H, s), 6.44 (1H, s),6.70 (1H, s), 7.21 (2H, s); m/z (EI) 301 (M⁺).

Step 3) Synthesis of5-Isopropyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione

The compound obtained in Step 2) (2.6 g, 8.6 mmol) was refluxed withacetyl bromide (30 ml) for 19 hr. The reaction mixture was allowed tocool to room temperature and the solvent was removed under reducedpressure. The resulting residue was purified by flash chromat ography(eluent-ethyl acetate:hexane=2:1) to afford 2.6 g (yield 96%) of thetitle compound as a white solid.

Preparation 23: Synthesis of5-Ethyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione (Compound(II-a-2))

The procedure of Preparation 22 was repeated using5-ethyl-2,4,6-trichloropyrimidine in place of5-isopropyl-2,4,6-trichloropyrimidine to prepare the title compound.

Preparation 24: Synthesis of5-Isopropyl-6-(3′-nitro-5′-methylbenzoyl)-2,4-pyrimidinedione (Compound(II-b-1))

Step 1) Synthesis of2,4-Dichloro-5-isopropyl-6-(α-cyano-3′-nitro-5′-methylbenzyl)pyrimidine

To a magnetically stirred DMF solution (30 ml) of3-nitro-5-methylphenylacetonitrile (2.64 g, 15 mmol) and5-isopropyl-2,4,6-trichloropyrimidine (4.05 g, 18 mmol) cooled in an icebath, 60% sodium hydride dispersion (1.15 g, 30 mmol) was addedportionwise under a nitrogen atmosphere. After stirring for 2 hr, thereaction mixture was allowed to warm to room temperature and stirred for16 hr. The reaction mixture was then neutralized with aqueous ammoniumchloride and ethyl ether was added thereto. The organic layer was washedwith water, dried over anhydrous magnesium sulfate, and filtered. Thesolvent was removed under reduced pressure and the resulting residue waspurified by flash chromatography (eluent-ethyl acetate:hexane=1:4) toafford 3.99 g (yield 73%) of the title compound as a white solid.

M.p.: 124 to 125° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.23 (3H, d, J=7.2 Hz),1.38 (3H, d, J=7.2 Hz), 2.51 (3H, s), 3.34 (1H, m), 5.60 (1H, s), 7.57(1H, s), 7.99 (1H, s), 8.07 (1H, s); m/z (EI) 365 (M⁺).

Step 2) Synthesis of2,4-Dimethoxy-5-isopropyl-6-(α-cyano-3′-nitro-5′-methylbenzyl)pyrimidine

To a stirred anhydrous methanol solution (60 ml) of the compoundobtained in Step 1) (3.65 g, 10 mmol), sodium methoxide (3.24 g, 60mmol) was added at room temperature under a nitrogen atmosphere andrefluxed for 24 hr. The reaction mixture was then allowed to cool toroom temperature and neutralized with excess ammonium chloride. Afterremoving the solvent, the resulting residue was purified by flashchromatography (eluent-ether:hexane=1:3) to afford 1.8 g (yield 50%) ofthe title compound as a light yellow solid.

M.p.: 134 to 135° C. ¹H-NMR (200 MHz, CDCl₃) δ 1.15 (3H, d, J=6.7 Hz),1.20 (3H, d, J=6.7 Hz), 2.49 (3H, s), 3.05 (1H, m), 4.00 (3H, s), 4.01(3H, s), 5.48 (1H, s), 7.62 (1H, s), 8.00 (2H, s); m/z (EI) 356 (M⁺).

Step 3) Synthesis of2,4-Dimethoxy-5-isopropyl-6-(3′-nitro-5′-methylbenzoyl)pyrimidine

To a stirred DMF solution (20 ml) of the compound obtained in Step 2)(1.7 g, 4.7 mmol), 60% sodium hydride dispersion (283 mg, 7.1 mmol) wasadded at room temperature under a nitrogen atmosphere. The mixture wasthen stirred in the presence of oxygen. After 5 hr, the reaction mixturewas neutralized with ammonium chloride and ethyl ether was addedthereto. The organic layer was washed with water, dried over anhydrousmagnesium sulfate, and filtered. The solvent was removed under reducedpressure and the resulting residue was purified by flash chromatography(eluent-dichloromethane:hexane=97:3) to afford 1.039 (yield 62%) of thetitle compound as a white solid.

M.p.: 111 to 112° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.21 (6H, d, J=6.9 Hz),2.54 (3H, s), 2.88 (1H, m), 3.93 (3H, s), 4.09 (3H, s), 8.05 (1H, s),8.27 (1H, s), 8.44 (1H, s); m/z (EI) 345 (M⁺).

Step 4) Synthesis of5-isopropyl-6-(3′-nitro-5′-methylbenzoyl)-2,4-pyrimidinedione

The compound obtained in Step 3) (630 mg, 1.8 mmol) was refluxed withconc. hydrochloric acid (6 ml) for 4 hr and the reaction mixture wasallowed to cool to room temperature. The precipitate was then collected,washed with distilled water and hexane, and dried to give 560 mg (yield98%) of the title compound as a white solid.

TABLE 2 Prep. No. Comp. Structure M.p. (° C.) ¹H-NMR  1 (A)

238-239 (200 MHz, CDCl₃/CD₃OD) δ: 1.16(6H, d, J=6.9Hz), 2.35-2.49(7H,m), 7.35(2H, s), 7.53(2H, s).  2 (B)

249-250 (200 MHz, CDCl₃/CD₃OD) δ: 0.97(3H, t, J=7.4Hz), 2.17(2H, q,J=7.4Hz), 2.39(6H, s), 7.32(1H, s), 7.50(2H, s).  3 (C)

251-252 (200 MHz, CD₃OD/DMSO-d₆) δ: 1.36(6H, d, J=6.9Hz), 2.38(1H, m),2.46(3H, s), 7.26(1H, d, J=9.0Hz), 7.43(1H, d, J=8.4Hz), 7.52(1H, s).  4(D)

235-236 (200 MHz, CD₃OD/DMSO-d₆) δ: 0.99(3H, t, J=7.4Hz), 2.17(2H, q,J=7.4Hz), 2.50(3H, s), 7.44(1H, d, J=9.4Hz), 7.59(1H, d, J=8.8Hz),7.70(1H, m).  5 (E)

233-234 (200 MHz, CDCl₃/CD₃OD) δ: 1.06(6H, d, J=7.0Hz), 2.32(1H, m),7.07(1H, m), 7.25-7.38(2H, m).  6 (F)

211-212 (200 MHz, CDCl₃/CD₃OD) δ: 0.88(3H, t, J=7.3Hz), 2.06(2H, q,J=7.3Hz), 7.06(1H, m), 7.32-7.37(2H, m)  7 (G)

220-221 (200 MHz, CD₃OD) δ: 1.16(6H, d, J=7.0Hz), 2.45(1H, m),7.61-8.02(5H, m)  8 (H)

218-219 (200 MHz, CD₃OD) δ: 0.98(3H, t, J=7.5Hz), 2.17(2H, q, J=7.5Hz),7.58-8.03(5H, m)  9 (I)

220-221 (200 MHz, CDCl₃/CD₃OD) δ: 1.17(6H, d, J=6.8Hz), 2.39(1H, m),8.21(1H, s), 8.37(2H, s). 10 (J)

227-228 (200 MHz, CDCl₃/CD₃OD) δ: 1.13(6H, d, J=7.0Hz), 2.35-2.50(4H,m), 7.42-7.72(4H, m), 9.82(1H, s). 11 (K)

236-237 (200 MHz, CDCl₃/CD₃OD) δ: 0.97(3H, t, J=7.5Hz), 2.18(2H, q,J=7.5Hz), 2.44(3H, s), 7.28-7.71(4H, m), 9.70(1H, s). 12 (L)

252-253 (200 MHz, CDCl₃/CD₃OD) δ: 1.11(6H, d, J=6.9Hz), 2.33(1H, m),7.61-7.73(3H, m). 13 (M)

242-243 (200 MHz, CDCl₃/CD₃OD) δ: 0.90(3H, t, J=7.5Hz), 2.07(2H, q,J=7.5Hz), 7.59(1H, t, J=1.8Hz), 7.67(2H, d, J=1.8Hz). 14 (N)

254-255 (200 MHz, CDCl₃/CD₃OD) δ: 1.17(6H, d, J=6.9Hz), 2.25-2.45(4H,m), 7.50-7.71(3H, m). 15 (O)

218-219 (200 MHz, CDCl₃/CD₃OD) δ: 1.10(6H, d, J=6.9Hz), 2.32-2.52(4H,m), 5.41(2H, d, J=47.0Hz), 7.51-7.70(3H, m), 9.15(1H, s), 9.66(1H, s).16 (P)

224-225 (200 MHz, CDCl₃/CD₃OD) δ: 0.98(3H, t, J=7.4Hz), 2.16(2H, q,J=7.4Hz), 2.47(3H, s), 5.43(2H, d, J=47.2Hz), 7.54-7.71(3H, m). 17 (Q)

229-230 (200 MHz, CD₃OD) δ: 1.20(6H, d, J=7.1Hz), 2.33(6H, s), 3.35(1H,m), 6.64(2H, s), 6.83(1H, s). 18 (R)

221-222 (200 MHz, CD₃OD) δ: 0.90(3H, t, J=7.4Hz), 2.17-2.25(8H, m),6.62(2H, s), 6.78(1H, s). 19 (S)

225-226 (200 MHz, CDCl₃) δ: 1.34(6H, d, J=7.0Hz), 2.35(6H, s), 3.11(1H,m), 7.14(1H, s), 7.16(2H, s), 9.30(1H, s). 20 (T)

224-225 (200 MHz, DMSO-d₆) δ: 1.17(6H, d, J=6.8Hz), 3.22(1H, m),7.42(2H, s), 7.56(1H, s), 10.96(1H, s), 11.18(1H, s). 21 (U)

224-225 (200 MHz, CDCl₃) δ: 1.14(3H, t, J=7.5Hz), 2.36(6H, s), 2.55(2H,q, J=7.5Hz), 7.06(1H, s), 7.16-7.26(3H, m), 9.04(1H, s) 22 (II-a-1)

224-226 (200 MHz, CDCl₃) δ: 1.12-1.33(6H, m), 2.02-2.15(3H, m), 2.31(6H,s), 2.90(1H, m), 6.99(3H, s) 23 (II-a-2)

238-239 (200 MHz, CDCl₃) δ: 0.93(3H, t, J=7.5Hz), 2.05-2.15(3H, m),2.24-2.40(8H, m), 6.94-6.99(3H, m) 24 (II-b-1)

254-256 (200 MHz, CDCl₃/CD₃OD) δ: 1.12(6H, d, J=7.0Hz), 2.40(1H, m),2.54(3H, s), 8.11(1H, s), 8.37(1H, s), 8.49(1H, s)

EXAMPLE 1 Synthesis of1-(4′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 1)

To a magnetically stirred DMF solution (5 ml) of compound (A) obtainedin Preparation 1 (286 mg, 1 mmol) maintained at room temperature, wereadded anhydrous potassium carbonate (276 mg, 2 mmol), lithium iodide(134 mg, 1 mmol), and 4-picolyl chloride hydrochloride (164 mg, 1 mmol),in this order. After stirring for 16 hr, the solvent was removed underreduced pressure and the resulting residue was purified by flashchromatography (eluent-ethyl acetate:hexane=3:1) to afford 120 mg (yield32%) of the title compound as a white solid.

M.p.: 264 to 265° C.; ¹H-NMR (200 MHz; CDCl₃) δ 1.12 (3H, d, J=6.7 Hz),1.23 (3H, d, J=6.7 Hz), 2.30-2.40 (7H, m), 4.66 (1H, d, J=16.3 Hz), 4.88(1H, d, J=16.3 Hz), 6.98-7.36 (5H, m), 8.41-8.44 (2H, m), 9.91 (1H, s);m/z (EI) 377 (M⁺).

EXAMPLE 2 Synthesis of 1-(3′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 2)

The procedure of Example 1 was repeated using 3-picolyl chloridehydrochloride in place of 4-picolyl chloride hydrochloride to preparethe title compound.

M.p.: 179 to 180° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.12 (3H, d, J=6.9 Hz),1.22 (3H, d, J=6.9 Hz), 2.20-2.38 (7H, m), 4.71 (1H, d, J=16.0 Hz), 4.93(1H, d, J=16.0 Hz), 7.09-7.56 (5H, m), 8.29-8.43 (2H, m), 10.18 (1H, s);m/z (EI) 377 (M⁺).

EXAMPLE 3 Synthesis of 1-(2′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 3)

The procedure of Example 1 was repeated using 2-picolyl chloridehydrochloride in place of 4-picolyl chloride hydrochloride to preparethe title compound.

M.p.: 214 to 215° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.12 (3H, d, J=6.9 Hz),1.23 (3H, d, J=6.9 Hz), 2.20-2.40 (7H, m), 4.77 (1H, d, J=16.8 Hz), 5.16(1H, d, J=16.8 Hz), 7.01-7.48 (6H, m), 8.36 (2H, m), 9.90 (1H, s); m/z(EI) 377 (M⁺).

EXAMPLES 4 to 65

The procedure of Example 1 was repeated to obtain the2,4-pyrimidinedione derivatives of Examples 4-65 shown in Table 3.

TABLE 3 Ex. No. A Z R¹ R² R³ R⁴ ¹H-NMR (200 MHz, CDCl₃) δ M.p. (° C.)  4O C═O

Ethyl CH₃ CH₃ 0.97(3H, t, J=7.3Hz), 2.05(1H, m), 2.20- 2.35(7H, m),4.70(1H, d, J=16.4Hz), 4.90(1H, d, J=16.4Hz), 6.98-7.01(2H, m), 7.27(1H,s), 7.34(2H, s), 8.41-8.44 (2H, m), 9.25(1H, s). 267-268  5 O C═O

Ethyl CH₃ CH₃ 0.95(3H, t, J=7.3Hz), 2.02(1H, s), 2.20-2.40(7H, m),4.72(1H, d, J=16.4Hz), 4.90(1H, d, J=16.4Hz), 7.14(1H, s), 7.34(2H, s),7.52(1H, m), 8.29-8.43(2H, m), 9.25(1H, s). 197-198  6 O C═O

Ethyl CH₃ CH₃ 0.95(3H, t, J=7.1Hz), 2.05(1H, m), 2.20-2.40(7H, m),4.81(1H, d, J=16.4Hz), 5.14(1H, d, J=16.4Hz), 7.01-7.52(6H, m), 8.40(1H,m), 9.11(1H, s). 235-236  7 O C═O

Isopropyl CH₃ F 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz),2.22-2.38(4H, m), 4.63(1H, d, J=16.3Hz), 4.94(1H, d, J=16.3Hz),7.00-7.36(5H, m), 8.41-8.45(2H, m), 9.56(1H, s). 207-209  8 O C═O

Isopropyl CH₃ F 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.27(1H, m),2.34(3H, s), 4.64(1H, d, J=15.6Hz), 5.00(1H, d, J=16.4Hz), 7.10-7.53(5H,m), 8.27-8.42(2H, m), 9.41(1H, s). 211-212  9 O C═O

Isopropyl CH₃ F 1.13(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz),2.20-2.35(4H, m), 4.69(1H, d, J=16.4Hz), 5.29(1H, d, J=16.4Hz),7.00-7.52(6H, m), 8.37(1H, m), 9.15(1H, s). 187-189 10 O C═O

Ethyl CH₃ F 0.98(3H, t, J=7.3Hz), 2.05(1H, m), 2.20- 2.37(7H, m),4.70(1H, d, J=16.4Hz), 4.92(1H, d, J=16.4Hz), 7.00-7.37(5H, m),8.44-8.46(2H, m), 10.39(1H, s). 233-234 11 O C═O

Ethyl CH₃ F 0.95(3H, t, J=7.3Hz), 2.02(1H, m), 2.05(1H, m), 2.33(3H, s),4.72(1H, d, J=16.4Hz), 5.02(1H, d, J=16.4Hz), 7.11-7.56(5H, m),8.30-8.44(2H, m). 189-190 12 O C═O

Ethyl CH₃ F 0.96(3H, t, J=7.3Hz), 2.03(1H, m), 2.22(1H, m), 2.33(3H, s),4.74(1H, d, J=16.4Hz), 5.23(1H, d, J=16.4Hz), 7.02-7.53(6H, m), 8.39(1H,m), 9.17(1H, s). 158-159 13 O C═O

Isopropyl F F 1.15(3H, d, J=7.0Hz), 1.23(3H, d, J=7.0Hz), 2.26(1H, m),4.63(1H, d, J=16.2Hz), 4.94(1H, d, J=16.2Hz), 6.97-7.26(5H, m),8.43-8.46(2H, m), 8.90(1H, s). 189-190 14 O C═O

Isopropyl F F 1.12(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz), 2.23(1H, m),4.63(1H, d, J=15.8Hz), 5.06(1H, d, J=15.8Hz), 7.01-7.54(5H, m), 8.26(1H,m), 8.42(1H, m), 9.49(1H, s). 227-230 15 O C═O

Isopropyl F F 1.15(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.23(1H, m),4.62(1H, d, J=16.6Hz), 5.31(1H, d, J=16.6Hz), 6.95-7.54(6H, m), 8.37(1H,m), 9.10(1H, s). 214-215 16 O C═O

Ethyl F F 0.97(3H, t, J=7.4Hz), 2.02(1H, m), 2.25(1H, m), 4.65-4.92(2H,m), 6.99-7.40(5H, m), 8.43-8.46(2H, m), 9.73(1H, s). 223-224 17 O C═O

Ethyl F F 0.96(3H, t, J=7.3Hz), 2.00(1H, m), 2.22(1H, m), 4.68(1H, m),5.04(1H, m), 7.03-7.27(4H, m), 7.54(1H, m), 8.28-8.44(2H, m), 9.89(1H,s). 217-218 18 O C═O

Ethyl F F 0.97(3H, t, J=7.5Hz), 2.01(1H, m), 2.22(1H, m), 4.76(1H, m),5.31(1H, m), 6.95-7.55(6H, m), 8.37(1H, m), 9.03(1H, s). 206-207 19 OC═O

Isopropyl Cl Cl 1.12(3H, d, J=6.9Hz), 1.25(3H, d, J=6.9Hz), 2.21(1H, m),4.59(1H, d, J=16.6Hz), 4.99(1H, d, J=16.6Hz), 6.98(2H, d, J=5.9Hz),7.55(3H, s), 8.44(2H, d, J=5.9Hz). 232-233 20 O C═O

Ethyl Cl Cl 0.98(3H, t, J=7.5Hz), 2.05(1H, m), 2.28(1H, m), 4.68(1H, d,J=16.5Hz), 5.02(1H, d, J=16.5Hz), 6.98(2H, d, J=5.9Hz), 7.54-7.74(3H,m), 8.45(2H, d, J=5.9Hz), 9.36(1H, s). 243-245 21 O C═O

Isopropyl CH₃ Cl 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz),2.20-2.38(4H, m), 4.61(1H, d, J=16.3Hz), 4.95(1H, d, J=16.3Hz),6.97-8.44(7H, m), 9.35(1H, s). 248-249 22 O C═O

Isopropyl CH₂F CH₃ 1.07(3H, d, J=6.7Hz), 1.18(3H, d, J=6.7Hz), 2.25(1H,m), 2.32(3H, s), 4.61(1H, d, J=16.4Hz), 4.84(1H, d, J=16.4Hz), 5.29(2H,d, J=47.2Hz), 6.97(2H, d, J=5.9Hz), 7.39-7.53(3H, m), 8.32(2H, d,J=5.9Hz). 190 (dec.) 23 O C═O

Ethyl CH₂F CH₃ 0.97(3H, t, J=7.5Hz), 2.04(1H, m), 2.25(1H, m), 2.36(3H,s), 4.68(1H, d, J=15.0Hz), 4.94(1H, d, J=15.0Hz), 5.33(2H, d, J=47.2Hz),6.98-7.01(2H, m), 7.42-7.54(3H, m), 8.39-8.42(2H, m), 9.48(1H, s).227-228 24 O O

Isopropyl CH₃ CH₃ 1.14(6H, d, J=7.1Hz), 2.27(6H, s), 2.84(1H, m),4.88(2H, s), 6.44(2H, s), 6.75(1H, s), 7.11(2H, dd, J=4.5Hz, J=1.6Hz),8.54(2H, dd, J=4.5Hz, J=1.6Hz), 9.79(1H, s). 213-215 25 O O

Ethyl CH₃ CH₃ 0.94(3H, t, J=7.5Hz), 2.21(2H, q, J=7.5Hz), 2.27(6H, s),4.92(2H, s), 6.45(2H, s), 6.76(1H, s), 7.13(2H, d, J=6.1Hz), 8.54(2H, d,J=6.1Hz), 8.95(1H, s). 229-230 26 O S

Isopropyl Cl Cl 1.21(6H, d, J=6.9Hz), 3.33(1H, m), 5.20(2H, s),6.81-7.11(5H, m), 8.43-8.46(2H, m), 9.70(1H, s). 198-199 27 O S

Isopropyl CH₃ CH₃ 1.26(6H, d, J=6.9Hz), 2.21(6H, s), 3.52(1H, m),5.25(2H, s), 6.65(2H, s), 6.80(1H, s, 7.01(2H, d, J=5.7Hz), 8.50(2H, d,J=5.7Hz), 10.82(1H, s). 186-187 28 O S

Ethyl CH₃ CH₃ 1.07(3H, t, J=7.5Hz), 2.23(6H, s), 2.73(2H, q, J=7.5Hz),5.21(2H, s), 6.68(2H, s), 6.82(1H, s), 6.98(2H, d, J=6.3Hz), 8.48(2H, d,J=6.3Hz), 8.97(1H, s). 191-192 29 O C═O

Isopropyl CF₃ CF₃ 1.14(3H, d, J=6.9Hz), 1.24(3H, d, J=6.9Hz), 2.18(1H,m), 4.51(1H, d, J=16.3Hz), 5.28(1H, d, J=16.3Hz), 6.95(2H, d, J=6.1Hz),8.07(1H, s), 8.11(2H, s), 8.37(2H, d, J=6.1Hz). 236-237 30 O C═O

Ethyl CF₃ CF₃ 0.97(3H, t, J=7.3Hz), 2.00-2.35(2H, m), 4.60(1H, m),5.22(1H, m), 6.94-6.98(2H, m), 8.07(3H, s), 8.35-8.38(2H, m), 9.73(1H,s). 208-209 31 O C═O

Isopropyl CF₃ CF₃ 1.14(3H, t, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.16(1H,m), 4.51(1H, d, J=16.4Hz), 5.51(1H, d, J=16.4Hz), 6.94-7.49(3H, m),8.03-8.32(4H, m), 9.61(1H, s). 185-186 32 O C═O

Isopropyl CH₃ H 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz),2.26-2.36(4H, m), 4.65(1H, d, J=16.0Hz), 4.86(1H, d, J=16.0Hz), 6.97(2H,d, J=5.9Hz), 7.25-7.60(4H, m), 8.38(2H, d, J=5.9Hz). 226-227 33 O C═O

Ethyl CH₃ H 0.97(3H, t, J=7.4Hz), 2.06(1H, m), 2.26(1H, m), 2.34(3H, s),4.72(1H, d, J=16.0Hz), 4.84(1H, d, J=16.0Hz), 6.99-7.02(2H, m),7.29-7.62(4H, m), 8.41-8.44(2H, m), 9.93(1H, s). 218-219 34 O C═O

Isopropyl H H 1.15(3H, d, J=6.9Hz), 1.25(3H, d, J=6.9Hz), 2.34(1H, m),4.70(1H, d, J=16.4Hz), 4.87(1H, d, J=16.4Hz), 6.99-7.82(7H, m),8.40-8.44(2H, m), 10.16(1H, s). 238-239 35 O C═O

Ethyl H H 0.97(3H, t, J=7.4Hz), 2.05(1H, m), 2.24(1H, m), 4.65-4.94(2H,m), 6.99-7.80(7H, m), 8.40-8.44(2H, m), 9.68(1H, s). 219-220 36 O C═O

Isopropyl CH₃ CH₃ 1.08(3H, d, J=6.9Hz), 1.21(3H, d, J=6.9Hz),2.20-2.40(7H, m), 4.59(1H, d, J=15.6Hz), 5.07(1H, d, J=15.6Hz),7.02-7.12(5H, m), 7.18(1H, s), 7.26(2H, s), 8.85(1H, s). 199-200 37 OC═O

Ethyl CH₃ CH₃ 0.93(3H, t, J=7.3Hz), 2.02(1H, m), 2.12-2.28(7H, m),4.64(1H, d, J=15.6Hz), 5.07(1H, d, J=15.6Hz), 7.02-7.26(8H, m), 8.97(1H,s). 221-222 38 O C═O

Isopropyl CH₃ CH₃ 1.12(3H, d, J=6.9Ha), 1.22(3H, d, J=6.9Hz),2.20-2.40(7H, m), 4.77(1H, d, J=16.0Hz), 4.98(1H, d, J=16.0Hz),7.23-7.32(5H, m), 8.00(2H, d, J=8.5Hz), 8.97(1H, s). 203-204 39 O C═O

Isopropyl CH₃ CH₃ 1.07(3H, d, J=6.9Hz), 1.20(3H, d, J=6.9Hz),2.20-2.40(7H, m), 3.69(3H, s), 4.50(1H, d, J=15.2Hz), 5.07(1H, d,J=15.2Hz), 6.57-7.31(7H, m), 8.74(1H, s). 156-157 40 O C═O

Isopropyl CH₃ CH₃ 1.10(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz), 2.11(3H,s), 2.25-2.38(7H, m), 4.34(1H, d, J=15.8Hz), 5.23(1H, d, J=15.8Hz),6.66(1H, s), 6.77(1H, s), 6.83(1H, s), 7.19(1H, s), 7.27(2H, s),8.72(1H, s). 226-227 41 O C═O

Ethyl CH₃ CH₃ 0.96(3H, t, J=7.5Hz), 2.08(1H, m), 2.20-2.40(7H, m),4.84(1H, d, J=16.6Hz), 5.00(1H, d, J=16.6Hz), 7.25-7.32(5H, m),7.98-8.05(2H, m), 9.43(1H, s). 230-231 42 O C═O

Ethyl CH₃ CH₃ 0.92(3H, t, J=7.3Hz), 2.05(1H, m), 2.10-2.40(7H, m),3.69(3H, s), 4.56(1H, d, J=15.4Hz), 5.07(1H, d, J=15.4Hz), 6.59-7.26(7H,m), 9.25(1H, s). 157-158 43 O C═O

Isopropyl CH₃ CH₃ 1.12(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz),2.22-2.40(7H, m), 4.54(1H, d, J=16.3Hz), 4.99(1H, d, J=16.3Hz),6.50-6.60(3H, m), 7.24(1H, s), 7.35(2H, s), 9.25(1H, s). 208-209 44 OC═O

Isopropyl CH₃ CH₃ 1.12(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.25(6H,s), 2.30(1H, m), 4.62(1H, d, J=15.9Hz), 5.33(1H, d, J=15.9Hz),7.19-7.30(3H, m), 7.51(2H, s), 7.58(1H, s), 9.92(1H, s). 184-185 45 OC═O

Isopropyl CH₃ CH₃ 1.05(3H, d, J=6.7Hz), 1.15(3H, d, J=6.7Hz),2.22-2.32(10H, m), 4.44(1H, d, J=16.0Hz), 4.90(1H, d, J=16.0Hz),6.69-6.72(2H, m), 7.16(1H, s), 7.19(2H, s), 8.20(1H, d, J=5.5Hz),8.82(1H, s). 269-270 46 O C═O

Isopropyl CH₃ F 1.15(3H, d, J=7.0Hz), 1.20(3H, d, J=7.0Hz), 2.21(1H, m),2.24(3H, s), 2.34(3H, s), 4.42(1H, d, J=16.2Hz), 4.96(1H, d, J=16.2Hz),6.70-7.26(5H, m), 8.21(1H, d, J=5.9Hz), 9.25(1H, s). 217-218 47 O C═O

Isopropyl CH₃ Cl 1.14(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz),2.22-2.38(4H, m), 2.41(3H, s), 4.46(1H, d, J=16.2Hz), 5.07(1H, d,J=16.2Hz), 6.77-8.30(6H, m), 9.50(1H, s). 253-254 48 O C═O

Isopropyl Cl Cl 1.15(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.23(1H, m),2.44(3H, s), 4.41(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.75-8.30(6H,m), 9.42(1H, s). 234-236 49 O C═O

Isopropyl CH₂F CH₃ 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz),2.26-2.37(7H, m), 4.48(1H, d, J=16.5Hz), 5.04(1H, d, J=16.5Hz), 5.31(2H,d, J=47.2Hz), 6.75-6.78(2H, m), 7.39-7.52(3H, m), 8.24(1H, m), 8.85(1H,s). 253-255 50 O C═O

Isopropyl CH₃ H 1.13(3H, d, J=7.0Hz), 1.23(3H, d, J=7.0Hz),2.24-2.39(7H, m), 4.54(1H, d, J=16.1Hz), 4.95(1H, d, J=16.1Hz),6.77-8.28(7H, m), 8.96(1H, s). 219-220 51 O C═O

Isopropyl CH₃ CH₃ 1.15(3H, d, J=6.7Hz), 1.24(3H, d, J=6.7Hz),2.28-2.42(7H, m), 4.55(1H, d, J=16.4Hz), 4.97(1H, d, J=16.4Hz),6.94-6.96(2H, m), 7.26(1H, s), 7.35(2H, s), 8.18(1H, m), 9.29(1H, s).253-254 52 O C═O

Ethyl CH₃ CH₃ 0.96(3H, t, J=7.5Hz), 2.05(1H, m), 2.20-2.30(7H, m),2.40(3H, s), 4.57(1H, d, J=16.3Hz), 4.96(1H, d, J=16.3Hz), 6.79-6.82(2H,m), 7.24(1H, s), 7.31(2H, s), 8.29(1H, d, J=4.6Hz), 9.55(1H, s). 211-21253 O C═O

Ethyl CH₃ F 0.97(3H, t, J=7.4Hz), 2.02(1H, m), 2.22-2.31(4H, m),2.42(3H, s), 4.56(1H, d, J=16.8Hz), 5.02(1H, d, J=16.8Hz), 6.79-7.33(5H,m), 8.30(1H, m), 9.64(1H, s). 183-184 54 O C═O

Ethyl CH₃ CH₃ 0.98(3H, t, J=7.5Hz), 2.10(1H, m), 2.25-2.32(7H, m),4.59(1H, d, J=15.6Hz), 4.96(1H, d, J=15.6Hz), 6.94-6.97(2H, m), 7.27(1H,s), 7.33(2H, s), 8.19(1H, m), 9.34(1H, s). 217-218 55 O C═O

Isopropyl CH₃ CH₃ 1.11(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz),2.22-2.38(13H, m), 4.37(1H, d, J=16.0Hz), 5.05(1H, d, J=16.0Hz),6.56(2H, s), 7.19(1H, s), 7.27(2H, s), 9.70(1H, s). 232-233 56 O C═O

Isopropyl F F 1.15(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.23(1H, m),2.36(6H, s), 4.34(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.58(2H, s),7.01-7.20(3H, m), 9.25(1H, s). 176-178 57 O C═O

Isopropyl Cl Cl 1.13(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.20(1H, m),2.35(6H, s), 4.22(1H, d, J=16.3Hz), 5.30(1H, d, J=16.3Hz), 6.54(2H, s),7.46(2H, s), 7.50(1H, s), 9.35(1H, s). 172-173 (foam) 58 O C═O

Isopropyl CH₂F CH₃ 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz),2.22-2.35(10H, m), 4.35(1H, d, J=16.0Hz), 5.13(1H, d, J=16.0Hz),5.31(2H, d, J=47.2Hz), 6.56(2H, s), 7.37-7.50(3H, m), 9.06(1H, s).197-198 (foam) 59 O C═O

Isopropyl Cl CH₃ 1.13(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz),2.20-2.35(10H, m), 4.32(1H, d, J=16.0Hz), 5.19(1H, d, J=16.0Hz),6.56(2H, s), 7.27-7.50(3H, m), 9.34(1H, s). 222-223 60 O C═O

Ethyl CH₃ CH₃ 0.95(3H, t, J=7.5Hz), 2.02(1H, m), 2.20-2.33(13H, m),4.45(1H, d, J=16.0Hz), 5.05(1H, d, J=16.0Hz), 6.59(2H, s), 7.22(1H, s),7.29(2H, s), 9.45(1H, s). 211-212 61 O C═O

Ethyl F F 1.15(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.23(1H, m),2.36(6H, s), 4.34(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.58(2H, s),7.01-7.20(3H, m), 9.25(1H, s). 176-178 62 O C═O

Isopropyl CH₃ CH₃ 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz),2.30-2.40(7H, m), 4.69(1H, d, J=16.4Hz), 4.86(1H, d, J=16.4Hz),7.27-7.37(5H, m), 8.52(1H, m), 9.50(1H, s). 236-238 63 O C═O

Isopropyl CH₃ Cl 1.16(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.30(1H,m), 2.40(3H, s), 4.77(2H, s), 7.27-7.56(5H, m), 8.56(1H, d, J=5.1Hz),9.27(1H, s). 220-221 64 O C═O

Isopropyl CH₃ NO₂ (CDCl₃/CD₃OD) δ 1.11(3H, d, J=7.1Hz), 1.23(3H, d,J=7.1Hz), 2.23(1H, m), 2.49(3H, s), 4.63(1H, d, J=16.2Hz), 4.98(1H, d,J=16.2Hz), 7.02(2H, d, J=5.7Hz), 7.84(1H, s), 8.27-8.35(4H, m). 256-25765 O C═O

Isopropyl CH₃ NO₂ 1.13(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.22(1H,m), 2.37(3H, s), 2.46(3H, s), 4.41(1H, d, J=16.2Hz), 5.25(1H, d,J=16.2Hz), 6.75-6.79(2H, m), 7.76(1H, s), 8.21-8.28(3H, m), 9.76(1H, s).237-238

EXAMPLE 66 Synthesis of 1-(4′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylphenylamino)-2,4-pyrimidinedione (Compound 66)

To a magnetically stirred DMF solution (10 ml) of compound (II-a-1)obtained in Preparation 22 (630 mg, 2 mmol) at room temperature, wereadded anhydrous potassium carbonate (552 mg, 4 mmol), lithium iodide(268 mg, 2 mmol), and 4-picolyl chloride hydrochloride (328 mg, 2 mmol).After stirring for 24 hr, the solvent was removed under reduced pressureand the resulting residue was purified by flash chromatography(eluent-ethyl acetate) to give 276 mg (yield 34%) of1-(4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione. The compound thusobtained was then refluxed in methanol (10 ml) with sodium methoxide(110 mg, 2 mmol) for 6 hr. The reaction mixture was allowed to cool toroom temperature and neutralized with excess ammonium chloride. Thesolvent was removed under reduced pressure and the resulting residue waspurified by flash chromatography (eluent-methanol:ether=8:92) to afford280 mg (yield 88%) of the title compound as a white solid.

M.p.: 272 to 273° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.20 (6H, d, J=6.9 Hz),2.24 (6H, s), 2.90 (1H, m), 4.90 (2H, s), 6.27 (2H, s), 6.61 (1H, s),7.04-7.06 (2H, m), 8.42-8.45 (2H, m); m/z (EI) 364 (M⁺).

EXAMPLE 67 Synthesis of 1-(4′-Picolyl)-5-ethyl-6-(3′,5′-dimethylphenylamino)-2,4-pyrimidinedione (Compound 67)

The procedure of Example 66 was repeated using compound (II-a-2)obtained in Preparation 23 in place of compound (II-a-1) to prepare thetitle compound.

M.p.: 250 to 251° C.; ¹H-NMR (200 MHz, CDCl₃/CD₃OD) δ 0.99 (3H, t, J=7.5Hz), 2.24 (6H, s), 2.37 (2H, q, J=7.5 Hz), 4.91 (2H, s), 6.31 (2H, s),6.62 (1H, s), 7.04-7.07 (2H, m), 8.40-8.43 (2H, m); m/z (EI) 350 (M⁺).

EXAMPLE 68 Synthesis of1-(N-oxo-4′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 68)

Compound 1 obtained in Example 1 (2.26 g, 6 mmol) was stirred withm-chloroperbenzoic acid (2.72 g, 9 mmol) in dichloromethane (120 ml) atroom temperature. After 6 hr, the solvent was removed and the residuewas purified by flash chromatography (eluent-chloroform:methanol=93:7)to afford 2 g (yield 84%) of the title compound as a white solid.

M.p.: 254 to 255° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.12 (3H, d, J=6.7 Hz),1.22 (3H, d, J=6.7 Hz), 2.25-2.36 (7H, m), 4.69 (2H, s), 7.05-7.41 (5H,m), 8.05-8.09 (2H, m), 9.52 (1H, s); m/z (EI) 393 (M⁺).

EXAMPLE 69 Synthesis of1-(N-oxo-3′-Methyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 69)

Compound 45 obtained in Example 45 (834 mg, 2.13 mmol) was stirred withm-chloroperbenzoic acid (969 mg, 3.2 mmol) in dichloromethane (40 ml) atroom temperature. After 5 hr, the solvent was removed and the residuewas purified by flash chromatography (eluent-ethyl acetate:methanol=7:1)to afford 860 mg (yield 99%) of the title compound as a white solid.

M.p.: 223 to 224° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.13 (3H, d, J=6.7 Hz),1.23 (3H, d, J=6.7 Hz), 2.25-2.40 (10H, m), 4.56 (1H, d, J=16.0 Hz),4.85 (1H, d, J=16.0 Hz), 6.93 (1H, m), 7.31 (1H, s), 7.37 (2H, s), 8.10(1H, m), 10.08 (1H, s); m/z (EI) 407 (M⁺).

EXAMPLE 70 Synthesis of 1-(N-oxo-3′,5-Dimethyl-4′-picolyl)-5-Isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-Pyrimidinedione (Compound 70)

Compound 55 obtained in Example 55 (840 mg, 2 mmol) was stirred withm-chloroperbenzoic acid (942 mg, 3 mmol) in dichloromethane (40 ml) atroom temperature. After 20 hr, the solvent was removed and the residuewas purified by flash chromatography(eluent-dichloromethane:methanol=15:1) to afford 800 mg (yield 95%) ofthe title compound as a white solid.

M.p.: 241 to 242° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.12 (3H, d, J=6.7 Hz),1.22 (3H, d, J=6.7 Hz), 2.30-2.34 (13H, m), 4.41 (1H, d, J=16.0 Hz),54.98 (1H, d, J=16.0 Hz), 6.80 (2H, s), 7.27 (1H, m), 7.34 (2H, s), 9.21(1H, s); m/z (EI) 421 (M⁺).

EXAMPLE 71 Synthesis of1-(N-oxo-3′,5′-Dimethyl-4′-picolyl)-5-isopropyl-6-(3′,-chloro-5-methylbenzoyl)-2,4-pyrimidinedione(Compound 71)

Compound 59 obtained in Example 59 (860 mg, 2 mmol) was stirred withm-chloroperbenzoic acid (942 mg, 3 mmol) in dichloromethane (40 ml) atroom temperature. After 21 hr, the solvent was removed and the residuewas purified by flash chromatography (eluent-ethyl acetate:hexane=10:1)to afford 870 mg (yield 98%) of the title compound as a white solid.

M.p.: 2 to 226° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.13 (3H, d, J=6.9 Hz),1.22 (3H, d, J=6.9 Hz), 2.22-2.36 (13H, m), 4.39 (1H, d, J=16.0 Hz),5.04 (1H, d, J=16.0 Hz), 6.80 (2H, s), 7.33-7.54 (3H, m), 9.14 (1H, s);m/z (EI) 441 (M⁺).

EXAMPLE 72 Synthesis of1-(3′-Acetoxymethyl-4′-picolyl)-5-Isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 72)

Compound 69 obtained in Example 69 (800 mg, 1.96 mmol) was dissolved inacetic anhydride (10 ml) and the solution was heated in an oil bath(120-140° C.) with stirring for 4 hr. The solvent was then removed underreduced pressure and the residue was purified by flash chromatography(eluent-ethyl acetate:hexane=2:1) to afford 150 mg (yield 17%) of thetitle compound as a syrup.

¹H-NMR (200 MHz, CDCl₃) δ 1.14 (3H, d, J=6.7 Hz), 1.28 (3H, d, J=6.7Hz), 2.16 (3H, s), 2.22-2.40 (7H, m), 4.68 (1H, d, J=16.2 Hz), 4.88 (1H,d, J=16.2 Hz), 5.08 (2H, s), 7.00-7.02 (2H, m), 7.26 (1H, s), 7.36 (2H,s), 8.44 (1H, m); m/z (EI) 449 (M⁺).

EXAMPLE 73 Synthesis of1-(3′-Acetoxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 73)

Compound 70 obtained in Example 70 (300 mg, 0.71 mmol) was dissolved inacetic anhydride (3 ml) and the solution was heated in an oil bath(120-130° C.) with stirring for 2 hr. The solvent was then removed underreduced pressure and the residue was purified by flash chromatography(eluent-ethyl acetate:hexane=1:1) to afford 110 mg (yield 33%) of thetitle compound as a foam.

¹H-NMR (200 MHz, CDCl₃) δ 1.13 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9Hz), 2.10-2.41 (10H, m), 4.53 (1H, d, J=16.0 Hz), 4.96 (1H, d, J=16.0Hz), 5.00 (2H, s), 6.78-6.81 (2H, m), 7.24 (1H, s), 7.34 (2H, s); m/z(EI) 463 (M⁺).

EXAMPLE 74 Synthesis of 1-(3′-Acetoxymethyl-5′-methyl-4-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione(Compound 74)

Compound 71 obtained in Example 71 (700 mg, 1.58 mmol) was dissolved inacetic anhydride (10 ml) and the solution was heated in an oil bath(120-130° C.) with stirring for 5 hr. The solvent was then removed underreduced pressure and the residue was purified by flash chromatography(eluent-ethyl acetate:hexane=2:1) to afford 115 mg (yield 15%) of thetitle compound as a foam.

¹H-NMR (200 MHz, CDCl₃) δ 1.14 (3H, d, J=6.9 Hz), 1.24 (3H, d, J=6.9Hz), 2.16 (3H, s), 2.20-2.32 (4H, m), 2.42 (3H, s), 4.48 (1H, d, J=16.3Hz), 5.00 (2H, s), 5.06 (1H, d, J=16.3 Hz), 6.76 (2H, d, J=5.9 Hz), 7.32(1H, s), 7.39 (1H, s), 7.52 (1H, s), 9.46 (1H, s); m/z (EI) 483 (M⁺).

EXAMPLE 75 Synthesis of1-(3′-Hydroxymethyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 75)

Compound 72 obtained in Example 72 (100 mg, 0.22 mmol) was stirred withammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature.After 6 hr, the solvent was evaporated in vacuo and the resultingresidue was recrystallized from methanol-chloroform to give 70 mg (yield77%) of the title compound as a white solid.

M.p.: 256 to 257° C.; ¹H-NMR (200 MHZ, DMSO-d₆) δ 1.05 (3H, d, J=6.8Hz), 1.11 (3H, d, J=6.8 Hz), 2.15 (1H, m), 2.28 (6H, s), 4.44 (2H, d,J=5.5 Hz), 4.59 (1H, d, J=16.7 Hz), 4.70 (1H, d, J=16.7 Hz), 5.35 (1H,t, J=5.5 Hz), 6.90 (1H, m), 7.15 (1H, s), 7.32 (1H, s), 7.55 (2H, s),8.25 (1H, m), 11.66 (1H, s); m/z (EI) 407 (M⁺).

EXAMPLE 76 Synthesis of1-(3′-Hydroxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 76)

Compound 73 obtained in Example 73 (150 mg, 0.32 mmol) was stirred withammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature.After 5 hr, the solvent was evaporated in vacuo and the resultingresidue was recrystalized from methanol-chloroform to give 100 mg (yield74%) of the title compound as a white solid.

M.p.: 234 to 236° C.; ¹H-NMR (200 MHZ, DMSO-d₆) δ 1.05 (3H, d, J=6.7Hz), 1.11 (3H, d, J=6.7 Hz), 2.15 (1H, m), 2.26 (9H, s), 4.37 (2H, d,J=5.3 Hz), 4.51 (1H, d, J=17.1 Hz), 4.72 (1H, d, J=17.1 Hz), 5.29 (1H,t, J=5.3 Hz), 6.72 (1H, s), 6.93 (1H, s), 7.30 (1H, s), 7.51 (2H, s),11.64 (1H, s); m/z (EI) 421 (M⁺).

EXAMPLE 77 Synthesis of1-(3′-Hydroxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione(Compound 77)

Compound 74 obtained in Example 74 (100 mg, 0.21 mmol) was stirred withammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature.After 6 hr, the solvent was evaporated in vacuo and the resultingresidue was recrystallized from methanol-chloroform to afford 78 mg(yield 85%) of the title compound as a white solid.

M.p.: 238 to 240° C.; ¹H-NMR (200 MHz, DMSO-d₆) δ 1.05 (3H, d, J=6.8Hz), 1.10 (3H, d, J=6.8 Hz), 2.11 (1H, m), 2.27 (3H, s), 2.49 (3H, s),4.37 (2H, d, J=5.7 Hz), 4.47 (1H, d, J=17.1 Hz), 4.82 (1H, d, J=17.1Hz), 5.27 (1H, t, J=5.7 Hz), 6.75 (1H, s), 6.93 (1H, s), 7.56 (1H, s),7.66 (1H, s), 7.74 (1H, s), 11.63 (1H, s); m/z (EI) 441 (M⁺).

EXAMPLE 78 Synthesis of1-(3′-Methoxycarbonyl-4′-picolyl)-5-isopropyl-6-(31,51-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 78)

Compound 62 obtained in Example 62 (100 mg, 0.25 mmol) was stirred withpotassium carbonate (138 mg, 1 mmol) and distilled water (0.5 ml) inmethanol (5 ml) at room temperature. After 18 hr, the reaction mixturewas acidified with glacial acetic acid and the solvent was evaporated invacuo. The resulting residue was purified by flash chromatography(eluent-ethyl acetate:hexane=4:1) to afford 74 mg (yield 68%) of thetitle compound as a white solid.

M.p.: 138 to 140° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.14 (3H, d, J=6.9 Hz),1.23 (3H, d, J=6.9 Hz), 2.28-2.38 (7H, m), 3.98 (3H, s), 4.68 (1H, d,J=16.0 Hz), 5.00 (1H, d, J=16.0 Hz), 7.21-7.33 (4H, m), 7.73 (1H, s),8.54 (1H, m), 9.45 (1H, s); m/z (EI) 435 (M⁺).

EXAMPLE 79 Synthesis of1-(3′-Carbamoyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 79)

Compound 62 obtained in Example 62 (60 mg, 0.15 mmol)was stirred withconc. sulfuric acid (1 ml) in an oil bath (80° C.). After 10 min, thereaction mixture was allowed to cool to room temperature and poured intodistilled water (10 ml). The resulting precipitate was collected byfiltration, washed with distilled water and hexane, and dried in vacuoto afford 38 mg (yield 61%) of the title compound as a white solid.

M.p.: 295 to 296° C.; ¹H-NMR (500 MHZ, DMSO-d₆) δ 1.03 (3H, d, J=6.9Hz), 1.10 (3H, d, J=6.9 Hz), 2.14 (1H, m), 2.25 (6H, s), 4.67 (1H, d,J=17.6 Hz), 4.75 (1H, d, J=17.6 Hz), 7.26 (1H, dd, J=5.0 Hz, J=1.7 Hz),7.29 (1H, s), 7.53 (2H, s), 7.63 (1H, d, J=2.5 Hz), 7.69 (1H, s), 8.04(1H, d, J=2.1 Hz), 8.40 (1H, d, J=5.0 Hz), 11.71 (1H, s); m/z (EI) 420(M⁺).

EXAMPLE 80 Synthesis of1-(3′-Carbamoyl-4′-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione(Compound 80)

Compound 63 obtained in Example 63 (90 mg, 0.21 mmol) was stirred withconc. sulfuric acid (1 ml) in an oil bath (80° C.). After 10 min, thereaction mixture was allowed to cool to room temperature and poured intodistilled water (10 ml). The resulting precipitate was collected byfiltration, washed with distilled water and hexane, and dried in vacuoto afford 87 mg (yield 92%) of the title compound as a white solid.

M.p.: 284 to 285° C.; ¹H-NMR (500 MHz, DMSO-d₆) δ 1.03 (3H, d, J=6.8Hz), 1.10 (3H, d, J=6.8 Hz), 2.12 (1H, m), 2.29 (3H, s), 4.68 (1H, d,J=17.3 Hz), 4.76 (1H, d, J=17.3 Hz), 7.29 (1H, dd, J=5.0 Hz, J=1.7 Hz),7.58 (1H, s), 7.63 (1H, d, J=2.5 Hz), 7.71 (1H, s), 7.74 (1H, s), 7.80(1H, s), 8.04 (1H, d, J=2.5 Hz), 8.41 (1H, d, J=5.0 Hz), 11.72 (1H, s);m/z (EI) 440 (M⁺).

EXAMPLE 81 Synthesis of1-(4′-Aminobenzyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione(Compound 81)

Compound 38 obtained in Example 38 (50 mg, 0.12 mmol) in methanol (5 ml)was stirred under an atmosphere of hydrogen in the presence of platiniumoxide catalyst (10 mg) at room temperature for 4 hr. The reactionmixture was filtered through celite and the solvent was removed underreduced pressure. The resulting residue was purified by flashchromatography (eluent-ethyl acetate:hexane=1:1) to afford 32 mg (yield70%) of the title compound as a yellow solid.

M.p.: 173 to 175° C.; ¹H-NMR (200 MHz, CDCl₃) δ 1.07 (3H, d, J=6.9 Hz),1.20 (3H, d, J=6.9 Hz), 2.20-2.40 (7H, m), 3.57 (2H, s), 4.46 (1H, d,J=15.2 Hz), 5.00 (1H, d, J=15.2 Hz), 6.35 (2H, d, J=8.3 Hz), 6.81 (2H,d, J=8.3 Hz), 7.21 (1H, s), 7.26 (2H, s), 8.86 (1H, s); m/z (EI) 391(M⁺).

Antiviral Activity and Cytotoxicity Test

The in vitro anti-HIV-1 assays were based on the inhibition of thevirus-induced cytopathic effect in MT-4 cells, as described in J. Med.Chem, 34, 349 (1991).

First, MT-4 cells were suspended in a culture medium at a concentrationof 1×10⁴ cells/ml and infected with 500 TCID₅₀ (50% cell cultureinfective dose)/well of HIV-1. Immediately after the virus infection,100 μl of the cell suspension was added to each of the wells of aflat-bottomed microtiter tray containing various concentrations of thetest compounds (1) to (81). After incubating for 4 or days at 37° C.,the number of viable cells was determined by the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)method, as disclosed in J. Virol. Methods, 20, 309 (1988).

The cytotoxicity of the compounds of the present invention was assessedin parallel with their antiviral activity. It was based on the viabilityof mock-infected host cells as determined by the MTT method (see J.Virol. Methods, 20, 309 (1988)). MKC-442(6-benzyl-1-ethoxymethyl-5-isopropyluracil) was employed as acomparative compound.

The results of the tests are shown in Table 4.

TABLE 4 Ex. No. (Compound) CD₅₀ (μg/ml)* ED₅₀ (μg/ml)** S.I.(CD₅₀/ED₅₀)***  1 22.6 0.0026 8,600  2 27.2 0.0036 7,578  3 26.1 0.00554,788  4 64.0 0.0027 23,940  5 18.7 0.012 1,553  6 28.2 0.0127 2,215  722.7 0.0034 6,597  8 28.16 0.008 3,451  9 40.5 0.0119 3,401 10 51.70.0101 5,133 11 47.4 0.0178 2,658 12 38.9 0.0542 716 13 42.3 0.01243,414 14 29.81 0.049 612 15 49.87 0.053 943 16 50.6 0.0601 841 17 74.30.112 663 18 93.2 0.1189 784 19 11.28 0.003 3,394 20 32.9 0.012 2,758 2155.07 0.0023 23,501 22 92.8 0.002 48,305 MKC-442 27.7 0.005 5,544 2352.1 0.003 15,245 24 15.8 0.010 1,628 25 >100 0.018 >5,557 26 6.5 0.0032,112 27 8.5 0.002 5,747 28 12.5 0.004 3,516 29 44.9 1.867 24 30 52.31.935 27 31 11.7 1.8 6 32 40.4 0.003 12,039 33 57.1 0.011 5,073 34 37.40.014 2,663 35 >100 0.0606 >1,650 36 8.01 0.004 2,170 37 5.78 0.0032,066 38 5.65 0.005 1,172 39 7.46 0.003 2,654 40 7.97 0.0348 229 41 4.630.009 497 42 2.14 0.002 921 43 7.16 0.0035 2,057 44 8.17 1.80 5 MKC-44227.7 0.005 5,544 45 >100 0.0098 >10,170 46 22.9 0.0024 9,691 47 93.750.0027 35,133 48 12.07 0.0030 4,021 49 64.39 0.0076 8,440 50 47.680.0029 16,351 51 17.1 0.0010 17,812 52 14.3 0.0010 14,684 53 37.8 0.003112,110 54 8.7 0.0017 4,992 55 9.9 0.0010 10,274 56 87.2 0.0044 19,648 579.46 0.0028 3,411 58 36.03 0.0025 14,300 59 8.68 0.0021 4,126 60 17.50.0026 6,739 61 37.5 0.0151 2,475 62 9.15 0.0016 5,858 63 8.55 0.00292,966 64 46 0.0096 4,801 65 44.08 0.0075 5,916 66 >100 0.08 >1,287MKC-442 27.7 0.005 5,544 67 54.5 0.42 130 68 56.9 0.0145 3,928 69 48.250.0125 3,853 70 25.84 0.0055 4,712 71 25.44 0.0082 3,092 72 38.49 0.00884,365 73 39.65 0.0067 5,903 74 28.81 0.0134 2,152 75 42.06 0.0031 13,44476 38.39 0.0084 4,561 77 23.51 0.0115 2,052 78 40.79 0.0075 5,41479 >100 0.0091 >10,942 80 27.83 0.0111 2,507 81 9.63 0.015 648 MKC-44227.7 0.005 5,544 Foot note: *CD₅₀: Cytotoxic concentration that causesdeath of MT-4 cells by 50% **ED₅₀: Effective concentration for theinhibition of the proliferation of HIV-1 by 50% ***S.I.: Selectivityindex = (CD₅₀/ED₅₀)

Antiviral Activity Against Mutant HIV-1

Antiviral activities of the inventive compounds were determined againstY181C which is representative HIV-1 mutant having high resistanceagainst anti-HIV-1 nonnucleosides, e.g., Nevirapine, by the MTT method.MKC-442 was employed as a comparative compound.

The representative results of the tests are shown in Table 5.

TABLE 5 Compound EC₅₀ (μM)* 1 0.005-0.014 4 0.010-0.041 MKC-442 13.4**Foot note: *EC₅₀: Effective concentration for the inhibition of theproliferation of mutant HIV-1 by 50% **Reference: J. Med. Chem., 42,4500 (1999)

As the above results show, the novel antiviral 2,4-pyrimidinedionederivatives of the present invention possess high antiviral activityagainst HIV-1, both wild-type and mutant HIV-1, and at the same timeshow high selectivity indices, i.e., low toxicity. The inventivecompounds can therefore be used as a drug for treating AIDS.

While the invention has been described with respect to the specificembodiments, it should be recognized that various modifications andchanges may be made by those skilled in the art to the invention whichalso fall within the scope of the invention as defined by the appendedclaims.

What is claimed is:
 1. A compound of formula(I) or a pharmaceuticallyacceptable salt thereof:

wherein: R¹ is a phenyl, pyridyl, or N-oxopyridyl group optionallyhaving one or two substituents selected from the group consisting ofhalogen, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with one or more halogenatoms, C₃₋₆ cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl, hydroxymethyl,azidomethyl, C₁₋₆ alkoxymethyl, C₁₋₆ acyloxymethyl, carbamoyloxymethyl,aminomethyl, N—(C₁₋₃ alkyl)aminomethyl, N,N-di(C₁₋₃ alkyl)aminomethyl,carboxy, C₁₋₆ alkoxycarbonyl, aziridine, amino, hydroxyethylamino,cyclopropylamino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,trifluoroacetamido, C₁₋₆ acylamido, carbamoyl, hydroxyethylcarbamoyl,cyclopropylcarbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl,aminocarbamoyl, dimethylaminocarbamoyl, hydrazino,1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; atetrahydropyridyl or piperidyl group optionally substituted with a C₁₋₆alkyl or C₁₋₆ alkoxycarbonyl group; a tetrahydropyranyl group; or atetrahydrofuryl group; R² is hydrogen, halogen, nitro, cyano, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, C₁₋₃alkylcarbamoyl, di(C₁₋₃ alkyl)carbamoyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl orbenzyl; R³ and R⁴ are each independently hydrogen, halogen, hydroxy,cyano, nitro, amino, acetamido, trifluoroacetamido, azido, C₁₋₃ alkyl,C₁₋₃ alkyl substituted with one or more halogen atoms, C₁₋₃alkoxycarbonyl, carbamoyl, C₁₋₃ alkylcarbamoyl, di(C₁₋₃ alkyl)carbamoylor C₁₋₃ alkoxy; A is O or S; and Z is O, C═O, NH or CH₂.
 2. The compoundof claim 1 wherein R¹ is a phenyl, pyridyl or N-oxopyridyl groupoptionally having one or more substituents selected from the groupconsisting of halogen, C₁₋₃ alkyl, C₁₋₃ alkyl substituted with one ormore halogen atoms, hydroxymethyl, acetoxymethyl, amino,cyclopropylamino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,trifluoroacetamido, C₁₋₃ acylamido, C₁₋₄ alkoxy, hydroxy, cyano, azido,nitro, carboxy, C₁₋₄ alkoxycarbonyl, carbamoyl, cyclopropylcarbamoyl,C₁₋₄ alkylcarbamoyl and di(C₁₋₄ alkyl)carbamoyl; R² is halogen, C₃₋₆cycloalkyl or C₁₋₃ alkyl; R³ and R⁴ are each independently hydrogen,halogen, cyano, nitro, amino, trifluoroacetamido, C₁₋₃ alkyl, C₁₋₃ alkylsubstituted with one or more halogen atoms, C₁₋₃ alkoxy or C₁₋₃alkoxycarbonyl; A is O or S; and Z is O, S, C═O or NH.
 3. The compoundof claim 1 wherein R¹ is a phenyl, pyridyl or N-oxopyridyl groupoptionally having one or more substituents selected from the groupconsisting of methyl, amino, nitro, methoxy, trifluoromethyl, fluoro,bromo, chloro, iodo, cyano, methylamino, ethylamino, isopropylamino,trifluoroacetamido, acetamido, hydroxymethyl, acetoxymethyl,Methoxycarbonyl and carbamoyl; R² is ethyl or isopropyl; R³ and R⁴ areeach independently hydrogen, chloro, fluoro, bromo, cyano, methyl,ethyl, isopropyl, fluoromethyl, trifluoromethyl, methoxy, amino ornitro; A is O; and Z is O, S, C═O or NH.
 4. A process for thepreparation of the compound of claim 1 which comprises coupling acompound of formula(II) with a compound of formula(III) in the presenceof a base:

wherein: R¹, R², R³, R⁴ and A have the same meanings as defined in claim1; Z′ is same as Z defined in claim 1 with the proviso that when A isoxygen, it can be a acetamido group; and Y is halogen, methanesulfonyl,toluenesulfonyl or trifluoromethanesulfonyl.
 5. A compound having theformula(II):

wherein: R′² is ethyl or isopropyl; R′³ is nitro, amino, acetamido,trifluoroacetamido or C₁₋₃ alkoxycarbonyl; R′⁴ is methyl or halogen; andZ″ is C═O, NH or acetamido.
 6. An antiviral composition against humanimmunodeficiency virus (HIV) comprising a therapeutically effectiveamount of the 2,4-pyrimidinedione compound or a pharmaceuticallyacceptable salt thereof of claim 1 as an active ingredient, and apharmaceutically acceptable carrier and/or adjuvant.